DIAGNOSTIC CHALLENGES IN HEMODIALYSIS PATIENTS

Diagnosis of Common Dermopathies in Dialysis Patients:

A Review and Update
Alina Markova, Jenna Lester, Joanne Wang, and Leslie Robinson-Bostom
Department of Dermatology, Alpert Medical School of Brown University, Providence, Rhode Island

ABSTRACT
Cutaneous abnormalities in patients with end-stage renal disease (ESRD) receiving hemodialysis or peritoneal dialysis
may demonstrate signs of their underlying condition or
reveal associated disease entities. While a thorough examination of the scalp, skin, mucosa, and nails is integral to establishing a diagnosis, certain conditions will resolve only with
dialysis or improvement of their renal disease and others
may not require or respond to treatment. Half and half nails,
pruritus, xerosis, and cutaneous hyperpigmentation are common manifestations in ESRD. With hemodialysis, uremic
frost is no longer prevalent in ESRD patients and ecchymo-

ses have decreased in incidence. Acquired perforating dermatoses are seen in over one-tenth of hemodialysis patients.
Metastatic calcinosis cutis and calciphylaxis are both rarely
reported, although the latter is seen almost exclusively in the
setting of hemodialysis. Diagnosis of nephrogenic systemic
brosis has historically been challenging; as such, new diagnostic criteria have been proposed. Blood porphyrin proles
are needed to differentiate between porphyria cutanea tarda
and pseudoporphyria. We will review and provide an update
on the aforementioned common cutaneous manifestations of
ESRD in patients receiving dialysis.

A variety of cutaneous disorders are more commonly

seen in patients with end-stage kidney disease than in the
general population; some are unique to this population.

and deposition of the excess pigment in the nail plate (2).

The exact pathophysiologic mechanism associated with
half and half nails is not well understood. Hypotheses
include the increased tissue concentration of b-melanocyte-stimulating hormone due to its poor dialyzability
(4). Lindsay, for whom this condition is named, believed
that it may be due to constricted venous return from the
nail beds leading to discoloration.
Beaus lines, Terry nails, Mees lines, and subungual hyperkeratosis should be included in the differential diagnosis as they also occur in patients with
ESRD (5). To distinguish these conditions, look for
the following clinical features on the nail: transverse
deep depressions (Beaus lines); single white transverse
band in nail plate (Mees lines); and proximal of
nail is pale and wide, with distal narrow and red
(Terry nails).
Half and half nails do not improve with dialysis but
sometimes improve with kidney transplantation (2).

Half and Half (Lindsays) Nails

Half and half nails are a fairly common disorder in
patients with ESRD. One study found the prevalence of
half and half nails to be 21% in patients on dialysis (1),
whereas other studies have found this change to be less
common (2,3). Half and half nails are seen in patients
with any degree of azotemia and appear as discoloration
of the nail with a proximal white portion and a distal
reddish-pink to brown portion (Fig. 1). The discoloration does not fade with pressure (4). The discoloration
of the nails does not change with nail growth, implying
that this is a problem that begins in the nail bed rather
than the matrix.
Histologically, an increase in the number of capillaries
and capillary wall thickness has been observed in the nail
bed (4). Leyden and Wood demonstrated melanin in the
distal portion of the nail plate, which suggests that acute
renal failure might lead to increased melanocyte activity

Uremic Frost
Uremic frost has become an uncommon cutaneous
presentation of severe renal failure as hemodialysis is
now widely available (1). One study found the prevalence of uremic frost to be 3% in their patient population
(1). Urate crystals are yellowish-white and appear on the
face, neck, and arms, and are due to eccrine deposition
of urea crystals (1). It used to be a common manifestation of chronic renal failure, but its incidence has
decreased due to the widespread use of hemodialysis (1).
White, friable, crystalline structures can be observed.

Address correspondence to: Leslie Robinson-Bostom,

Department of Dermatology, APC-10, Rhode Island Hospital, 593 Eddy St., Providence, RI 02903. Tel.: (401) 444-7139,
Fax: (401) 444-7105, or
e-mail: lrobinson-bostom@lifespan.org.
Seminars in DialysisVol 25, No 4 (JulyAugust) 2012
pp. 408418
DOI: 10.1111/j.1525-139X.2012.01109.x
2012 Wiley Periodicals, Inc.
408

409

DIAGNOSIS OF COMMON DERMOPATHIES IN DIALYSIS PATIENTS

These can also be diluted in normal saline and tested to

reveal elevated urea nitrogen levels, comparable to similarly increased blood levels (6).
Signicant renal impairment reduces clearance of urea
and other waste products and as a result, these
substances are secreted in sweat and crystallize upon
evaporation (7,8).
Retention keratosis, atopic dermatitis, and postinammatory desquamation should be included in the
differential diagnosis (6). Atopic dermatitis in adults presents with pruritus and ill-dened scaly pink plaques,
involving exural area. Postinammatory desquamation
presents as ne desquamation and scale, similar to peeling after a sunburn. Considering the decreased incidence and prevalence of uremic frost as hemodialysis
has become more widely available, hemodialysis can be
considered preventative.
Pruritus
Pruritus is one of the most characteristic features of
chronic kidney disease (CKD) (1). One study found pruritus to exist in 53% of its patient population (1).
Another study noted a higher percentage of pruritus in
patients with more advanced CKD: 18% of stage 3,
26% of stage 4, 42% of stage 5, 58% of stage 5 CKD on
maintenance hemodialysis for 1 month or greater
(9).Pruritus in dialysis patients is most commonly localized to the back, abdomen, or head. A generalized distribution is less frequently seen (4). Pruritus can be a
temporary condition lasting only a few months, but
more commonly affects patients for more than 1 year.
Pruritus may be clinically evidenced via secondary
changes such as excoriations, lesions of lichen simplex
chronicus, koebnerization of acquired perforating dermatoses, and prurigo nodularis (10). Atrophy of adnexal
structures including sebaceous glands may be seen in
patients with uremic pruritus. Additionally, there may
be microangiopathy with necrosis of endothelial cells
(10).
The mechanisms for this condition are not well understood. It is hypothesized that uremic pruritus is caused
by the metabolic disequilibrium of CKD (4). Others propose that a poorly dialyzable substance is responsible
for uremic pruritus by its systemic accumulation but
resolves with renal transplantation (4). It has been proposed as a manifestation of multisystem dysfunction
that is comorbid with renal failure (4). Proinammatory
mediators such as Th1 and interleukin-2 may play a role
in pruritus (4). Hypercalcemia and hyperphosphatemia
with secondary deposition of calcium phosphate crystals
in the skin may also contribute to itch (4).While uremia
may cause pruritus, other etiologies of pruritus must also
be ruled out. The patient must be evaluated for endocrine disorders, atopic dermatitis, infestations, psychiatric disorders (e.g., delusions parasitosis), contact
dermatitis, and allergic reactions to the dialysate (10).
Topical capsaicin cream (0.025%) has been shown to
be effective with limited adverse events. It diminishes
Substance P and prevents its reaccumulation. UVB
phototherapy has demonstrated variable degrees of

effectiveness (4). Although the exact mechanism by

which UVB phototherapy improves pruritus is not fully
understood, it appears to suppress histamine release as
well as deactivate circulating pruritogenic substances.
UVB phototherapy increases the risk for skin cancer,
especially in fair-skinned patients who will subsequently
receive a renal transplant. Naltrexone, an opiate agonist,
has noted efcacy in the treatment of pruritus (4). A pilot
study on the use of urea 10% lotion with dexpanthenol,
a moisturizer, showed signicant improvement in skin
itch (11).
Xerosis
Xerosis cutis, or dryness of the skin, is one of the
most common cutaneous abnormalities seen in
chronic renal failure. One study of 100 hemodialysis
patients noted 79% had xerosis cutis, making it the
most common cutaneous condition in this patient
group (1). Another paper reported that 5085% of
patients on maintenance dialysis suffer from xerosis
(12). Xerosis can be generalized or localized. It is
most often observed on the extremities (9). Not only
is xerosis bothersome to the patient but it also
increases the likelihood of infection by delaying
wound healing (13). Xerosis is caused by a reduction
in size of eccrine sweat glands and atrophy of sebaceous glands, at times attributed to the use of diuretics (1,13). Xerosis is predominantly seen over extensor
surfaces of forearms, legs, and thighs (1), and can
present with pruritus although it has a pathophysiology distinct from uremic pruritus. Histologically,
there is atrophy of the pilosebaceous follicles and
eccrine sweat glands (14).
The differential diagnosis includes icthyosis or any
process that would cause dry skin including pruritus and
insufcient use of emollients. Ichthyosis can be acquired
or inherited in an autosomal dominant or recessive fashion. Ichthyosis vulgaris is the most common form seen
and presents with sh-like scales sparing exural
surfaces.
A double-blind study showed that using a topical
emollient containing endocannabinoids improves itch
and xerosis (15). Additionally, a pilot study examining
the use of urea 10% lotion with dexpanthenol in xerosis
showed efcacy in decreasing scaling, roughness, redness,
and cracks (16). Patients should also be advised to avoid
excessive hand washing or showering as the dry skin can
be irritated by the accumulation of soap (12). Patients
should apply daily emollients to moist or wet skin (12).
Cutaneous Hyperpigmentation
Hyperpigmentation is a fairly common change seen
in patients with ESRD and can include either
increased melanin or yellowish hue (1). Twenty percent of patients in one study of 100 CKD patients
over the course of 1 year experienced hyperpigmentation; of note, this was the second most common
nding in this study population (11).This condition

410

Markova et al.

presents with macular darkening of the palms, soles

of the feet, and diffuse hyperpigmentation of mucosal
surfaces (13).On histologic examination of the skin,
deposition of melanin in the basal layer and supercial dermis may be noted (17).
The exact mechanism for this nding is unknown, but
some suggest that the accumulation of middle molecular
weight substances may result in increased skin pigmentation (18). Substances such as urochrome pigments, carotenoids, and a and b melanocyte-stimulating hormone
may be responsible for the increased pigmentation
observed in this condition (19). The differential diagnosis includes sun exposure and Addisons Disease (20).
Online hemodialtration worked more effectively
than hemodialysis in reducing skin pigmentation in sunexposed areas. Possible increased clearance of middle
molecular weight substances by hemodialtration may
reduce their accumulation and thus reduce hyperpigmentation. To avoid pigment changes, patients
with ESRD should be advised to use sunscreen, wide
brimmed hats, and sun protective clothing (21).

not completely eliminated with initiation of dialysis

(23). Nevertheless, treatments for reduction in ecchymoses include dialysis, especially peritoneal dialysis
as it does not require anticoagulation therapy. An
increase in tissue plasminogen activator activity postdialysis has been noted (25).
Estrogen has also been shown to decrease bleeding
abnormalities in renal failure by improving platelet reactivity by increasing beta thromboglobulin and thromboxane A2 concentrations in blood (26) and decreasing
nitric oxide generation, both of which contribute to
increased clotting activity (23). Desmopressin (synthetic
vasopressin) and cryoprecipitate are also therapeutic
options, but are used in the acute setting of severe hemorrhage or as prophylaxis for a renal biopsy (23) or other
surgical procedure. Additionally, a hematocrit greater
than 30% has been shown to improve bleeding time in
patients with severe ESRD, thus treating anemia might
concurrently help manage ecchymoses (23).
Follicular Hyperkeratosis

Ecchymosis
Ecchymoses in ESRD are not uncommon and can be
detected frequently in the skin and oral mucosa (22).
Although some studies report a lower incidence of
ecchymoses as dialysis has become more widely used
(23), in clinical practice, the incidence of ecchymoses has
appeared to remain constant. An ecchymosis is characterized by a purple skin discoloration due to intradermal
or subcutaneous bleeding, which fades to a yellow-green
color over 12 weeks (Fig. 2). Prolonged bleeding from
venipuncture sites, epistaxis, GI bleeding, or gingival
bleeding may be seen in patients demonstrating ecchymoses (23). An ecchymosis demonstrates extravasated
red blood cells in the dermis or subcutis.
Ecchymosis and the other bleeding abnormalities
are often seen with ESRD due to preexisting global
platelet dysfunction. To form a functioning clot,
platelets must aggregate at the endothelium and
release ADP and serotonin, which recruit more platelets to the damaged vessel wall (23). In ESRD, the
ability of platelets to store ADP and serotonin factors
is diminished. Therefore, platelets are less able to
aggregate at the endothelium leading to bleeding
disorders. Additionally, thrombocytopenia may be
seen in advanced renal disease (24). The differential
diagnosis includes trauma, inherited coagulation disorders such as hemophilia A or B, anticoagulation
therapy, solar purpura, immune thrombocytopenia,
and thrombotic thrombocytopenic purpura. A history
of trauma will help rule out traumatic ecchymoses or
solar purpura in addition to appropriate laboratory
tests to evaluate for any coagulopathies.
Urea, creatinine, phenol, phenolic acid, and guanidinosuccinic acid (GSA) are elevated in ESRD, which
contribute to platelet dysfunction (23). However,
serum levels of these toxins do not correlate with
bleeding time and thus dialysis is not a denitive
treatment for this disorder as the risk for bleeding is

Follicular hyperkeratosis is overproliferation of keratin in the hair follicles. There are many different types of
follicular hyperkeratosis, such as familial, sporadic,
malignancy associated, postinammatory, postirradiation; however, it may be challenging to distinguish
between these types both clinically and histologically
(27). It is also difcult to attribute one histological form
of hyperkeratosis to ESRD. Non-neoplastic follicular
hyperkeratosis is often associated with renal failure (27).
The spicules composing hyperkeratosis have digitatelike projections and can appear across the face, neck, and
chest. Histologically, spicules show abnormal keratinization with columns of orthokeratosis with focal and
admixed serum and inammatory cells. Eosinophilic
material deposited in stratum corneum, spinosa, and
granulosa is visible with H&E stain. IgG kappa is found
in epidermis and upper dermis and in the serum (27). The
etiology of follicular hyperkeratosis is unknown (28).
Follicular hyperkeratosis is nonspecic for ESRD;
therefore, it is important to develop a broad differential
diagnosis in order to rule out any other potential systemic abnormalities. The differential includes malignancy-associated conditions such as multiple myeloma
with amyloidosis, melanoma, familial or sporadic hyperkeratosis, polycystic kidney disease, pellagra, zinc deciency, hyperlipoproteinemia, and postirradiation (27).
Twelve percent ammonium lactate cream or lotion
or urea compounds may improve the follicular
hyperkeratosis.
Acquired Perforating Dermatoses
Acquired perforating dermatoses (APD) are a broad
spectrum of disorders where transepidermal elimination
of material from the dermis is seen with minimal damage
to the surrounding structures. APD is most commonly
seen in patients with end-stage renal disease or diabetes
(29,30). The clinical and histologic features of APD may

DIAGNOSIS OF COMMON DERMOPATHIES IN DIALYSIS PATIENTS

resemble any of the four primary perforating skin disorders: elastosis perforans serpiginosa, reactive perforating
collagenosis, perforating folliculitis, or Kyrles disease.
Up to 11% of hemodialysis patients develop APD
(29). In a Turkish study, nearly three-quarters of patients
with APD had CKD, 50% had diabetes, and 9.1% were
renal transplant recipients (30). All of the patients with
renal failure were on dialysis and the disease is suspected
to be linked to the dialysis treatments (30). APD arises in
adults (mean age 48 years), most commonly in the setting of diabetes mellitus or chronic renal failure (30).
APD is characterized by scattered cone-shaped and
plugged hyperkeratotic papules, plaques, and nodules in
areas predisposed to supercial trauma and friction
(e.g., extensors) (29). Lesions may be linearly arranged
secondary to koebnerization (29) (Figs. 3 and 4). Severe
pruritus is frequently reported (29).
Histopathology is required to establish a diagnosis of
APD (31). Skin biopsy reveals an epidermal invagination or dilated hair follicle with a keratotic plug
consisting of keratin, collagen or elastic bers and neutrophils (29,30). The pathophysiology of APD is not well
understood, but may be secondary to poor healing in
diabetes-induced microangiopathy or underlying renal
disease (29). Scratching-induced local trauma or dermal
necrosis, challenged by microvasculopathy, results in
extrustion of dermal material through the epidermis
(32). A foreign body reaction to altered dermal collagen
and calcium salt deposition in certain patients is also
suspected as a possible etiology of APD (32).
Skin biopsy is diagnostic for APD (29). Other
perforating dermatoses should be considered. Prurigo
nodularis, folliculitis, arthropod bites, multiple keratoacanthomas, psoriasis, and lichen planus may clinically
mimic APD and should be excluded (33).
A variety of conventional treatment options have
produced equivocal results in APD. Topical and systemic retinoids, topical corticosteroids and keratolytics,
ultraviolet B phototherapy, psoralen plus ultraviolet A,
allopurinol, cryosurgery, and photodynamic therapy
may be considered in the management of APD (34).
Metastatic Calcinosis Cutis
Metastatic calcinosis cutis (MCC), a subtype of calcinosis cutis, is a rare manifestation of systemic calcinosis where insoluble calcium and phosphate salts are
deposited in the dermis and subcutaneous tissue
(35,36). MCC is a late complication of chronic renal
failure (36). While calcinosis cutis is found in approximately 1% of patients with ESRD on dialysis annually, MCC is rarely reported (37). MCC has been
reported in genders and ages ranging from infants to
the elderly (36). Risk factors for the broader calicinosis
cutis were female gender, low levels of serum albumin,
high serum phosphate or total alkaline phosphatase
levels, and morbid obesity (35). Usually, painless exural inltrating plaques appear at periarticular sites;
the size and number of these calcications correlate
with the degree of hyperphosphatemia (29,35,38).
Unlike calciphylaxis, this benign nodular calcication

411

does not result in tissue necrosis (35,38). A white

chalky substance may be expressed through the skin
(29) (Fig. 5).
Calcium deposition is seen in the dermis and subcutis with surrounding foreign body giant cells and inammation (29). Although hematoxylin and eosin
stain is often adequate to visualize the calcium deposits, Von Kossa stains calcium black and may better
highlight the deposits (29). Hyperphosphatemia and
hypercalcemia both contribute to the development of
calcinosis cutis (36,38). However, it is likely that biologic factors in the microenvironment rather than
physical chemical precipitation are much more important determinants of this disorder. Little is known of
the nature of these factors.
Distinguishing the subtype of calcinosis cutis
through patient history of other underlying conditions,
location of lesions, and time course is vital for proper
therapy. Cutaneous calcications may also be seen
in scleroderma, subepidermal calcied nodules, and
tumoral calcinosis. There are no gold standard treatments for MCC. Lesions often regress with normalization of the serum calcium and phosphate levels and
therapy should be accordingly targeted (29,35). In the
setting of secondary hyperparathyroidism with refractory MCC, parathyroidectomy may allow for cure
(29,39).
Calciphylaxis (Calcific Uremic Arteriolopathy)
Calciphylaxis (calcic uremic arteriolopathy) is a
subtype of calcinosis cutis where calcication of small
vessels in the dermis and subcutaneous fat leads to cutaneous ischemia, tissue infarction, and necrosis (35). This
disease occurs almost exclusively in patients with ESRD,
most of whom are on hemodialysis; peritoneal dialysis
has been reported to pose an even greater risk (29,35).
Calciphylaxis occurs in approximately 14% of patients
on dialysis or with renal transplant. The mean patient
age is 48 years, with a higher incidence in women and
Caucasians (40). Risk factors include hyperparathyroidism, end-stage renal disease, elevated calcium-phosphate
product >70, and vitamin D exposure. Additionally,
obesity, liver disease, and immunosuppression are
among multiple challenging agents reported in patients
predisposed to this disease (41).
In calciphylaxis, exquisitely painful, violaceous reticulated plaques progress to nonhealing, deep, stellate
ulcers that usually become gangrenous (35) (Fig. 6).
Patients usually have multiple lesions, most commonly
on the lower legs and occasionally on the penis, digits,
and internal organs (35). Laboratory values within normal limits have been found in patients with calciphylaxis
and do not exclude this diagnosis. Of note, the calciumphosphate product has an overall specicity of 21%;
and when greater than 70 mg2 dl2, it has a sensitivity of
over 95%. However, 51% of calciphylaxis cases had a
product less than 50 mg2 dl2 (42). Additionally, 35% of
calciphylaxis cases on dialysis has a serum aluminum
level greater than 25 ng ml as compared to 11% of dialysis controls (42).

412

Markova et al.

Fig. 4. Acquired perforating disorder showing closer view of

nodules with central keratotic plug.

Fig. 1. Lindsay nails (half and half nails).

Fig. 5. Idiopathic calcinosis cutis showing white deposits and

one supercial ulceration.

Fig. 2. Ecchymosis on forearm.

Fig. 6. Calciphylaxis with central black eschar and surrounding

livedo reticularis.

Fig. 3. Acquired perforating disorder showing keratotic papules

in a linear distribution (koebnerization).

A wedge biopsy may be preferable to a punch biopsy

for adequate sampling (29). Calcic deposits are seen in
the medial layer of small to medium blood vessels of
the reticular dermis and subcutaneous fat (35). Intra-

DIAGNOSIS OF COMMON DERMOPATHIES IN DIALYSIS PATIENTS

mural brin thrombi are also seen in the dermis and

subcutaneous tissue. Lobular fat necrosis, with
increased neutrophils, lymphocytes, and foamy histiocytes should be observed (35). The etiology of calciphylaxis is controversial with several molecular
mechanisms hypothesized to play a role in its pathogenesis. Osteogenic markers (e.g., osteopontin, bone morphogenic protein 4) are often elevated and up-regulated
leading to increased vascular smooth muscle and periarterial dermal cell calcication (29,41). Warfarin inhibits
vitamin K-dependent gamma carboxylation, resulting
in increased calcication in patients on this therapy
(41,43). Additionally, ESRD patients do not effectively
remove excess phosphorus, thus stimulating extraosseous calcication. Vessel brosis, intimal hyperplasia,
and luminal narrowing due to vascular calcication
increase risk for sudden vascular occlusion and thrombosis, leading to calciphylaxis. Acute thrombosis of the
vessel results in painful ischemic purpura, whereas vascular stenosis progresses asymptomatically (35).
Antiphospholipid syndrome, radiation arteritis,
vasculitis, dystrophic calcication, cholesterol emboli,
panniculitis, purpura fulminans, warfarin or heparin
necrosis, pyoderma gangernosum, and levamisole toxicity should be considered in evaluating retiform purpura
(44).
Calciphylaxis is a disease with high morbidity and
mortality and few effective treatments. Supportive care
should emphasize aggressive wound debridement with
systemic pain management (45). Sepsis is the most common cause of mortality in these patients, and thus it is
important to monitor the patient for signs of infection at
the wound site. Surgical debridement of necrotic tissue,
systemic antibiotics, hydrocolloid dressings may be
attempted; however, there is a lack of standardized,
controlled indications for wound debridement (42).
Minimization of risk factors suspected to aggravate
calciphylaxis is necessary. A low phosphate diet
(43 mg day), and low calcium dialysate, in addition to
normalization of the calcium and phosphate levels (i.e.,
calcium-phosphate product less than 55 mg2 dl2) via
noncalcium-based phosphate binders (sevelamer) (45).
Sodium thiosulfate infusion 25 g IV over 30
60 minutes three times weekly has been reported to
have greatest success in improving lesions and reducing pain within 8 weeks; this treatment should be
continued for at least 2 months beyond complete resolution of lesions (45). Cinacalcet has been approved
for secondary hyperparathyroidism in chronic kidney
disease on dialysis; however, pain relief and ulcer
healing may take weeks to months (45). Bisphosphanates have produced favorable outcomes in several
patients, whereas reports of systemic corticosteroids
have been equivocal (45). Parathyroidectomy has produced signicant variability in postsurgical outcomes,
but may be considered in patients with hyperparathyroidism refractory to medical therapy and local
wound care (42). This surgical intervention may be
detrimental in patients with low PTH levels, and
should be considered with caution (42). Hyperbaric
oxygen therapy may be considered if medical and
surgical management is ineffective (45).

413

Nephrogenic Systemic Fibrosis

Nephrogenic systemic brosis (NSF) is a generalized
brotic disorder in the setting of renal dysfunction, rst
described as a scleromyxedema-like cutaneous disease in
renal-dialysis patients in 2000 and later termed nephrogenic brosing dermopathy (46,47). With reports
demonstrating extra-cutaneous involvement (e.g., heart,
lungs, kidney), this entity was appropriately renamed
NSF (48). While the pathogenesis of NSF is thought to
be multifactorial, nearly all known cases of NSF have
been reported in patients with exposure to gadolinium
contrast-enhanced MRI or MRA within 23 months of
symptoms onset, suggesting this agent as a possible trigger (49,50). Acute or chronic renal dysfunction and
background inammation play a signicant role in the
development of NSF, while liver disease, erythropoietin,
and acidosis are suspected contributors (50).
NSF is extremely rare, with reported risk ranging
from 0.01% to 0.02% in ESRD patients on dialysis (51).
An Auckland study reported the risk of NSF to be signicantly higher at 0.67% in patients with history of
exposure to any gadolinium-based contrast agents (51).
The absolute risk of NSF in a patient with any gadolinium agent exposure has been reported to range 1.13
3.4% (5154). In the Auckland study, all ve cases of
NSF were in patients with exposure to gadodiamide,
while there were no recognized cases in patients exposed
to other gadolinium agents (49). NSF has no predilection for age, gender, race, or geographic location (55).
Careful clinicopathologic correlation is required for
accurate diagnosis of NSF; that is, there is no gold standard laboratory test used for diagnosis (49). Scored clinical and histopathologic criteria have been proposed as a
possible diagnostic standard in the setting of chronic
kidney disease (49). Major criteria include patterned plaques, cobblestoning, joint contractures, or marked
induration; and minor criteria consist of linear banding,
supercial plaques patches, dermal papules, or scleral
plaques (49) (Figs. 7 and 8). In this scoring system, a
patient with >1 major criterion is highly consistent with
NSF; =1 major criterion, is consistent; 1 minor
criterion is suggestive; and 01 minor criteria is inconsistent (49).
The clinical criteria should be supported by histologic
ndings; specically, increased dermal cellularity
(exceeding 1926 HPF; mean = 70.8 HPF), CD34+
cells with tram-tracking, thick and thin collagen bundles,
preserved elastic tissue, septal involvement, or osseous
metaplasia (49,56). However, the histologic ndings are
highly variable and often subtle (56).
Several pathomechanisms have been hypothesized
to play a role in the development of NSF, such as
up-regulation of osteopontin, and imbalance between
matrix metalloproteinases and tissue inhibitor of
metalloproteinase 1 (57). Gadolinium precipitates are
produced by transmetallation of free or chelated gadolinium and activate macrophages and broblasts
(57). Circulating brocytes may endocytose gadolinium-based contrast agents (GBCA), triggering a
brotic expression in broblasts. This leads to the
activation of the nuclear factor kappa B pathway and

414

Markova et al.

Fig. 10. Porphyria cutanea tarda. Note the white milia and tensa
bulla.

Fig. 7. Nephrogenic systemic brosis with diffuse sclerosis and

exural contracture. Note proximal AV stula.

Fig. 11. Porphyria cutanea tarda. Note the hypertrichosis most

prominent along the jawline.

Fig. 8. Nephrogenic systemic brosis with sclerosis of dorsal

hand and contracture.

Fig. 9. Porphyria cutanea tarda. Note the milia and large tense
bulla.

interaction with transforming growth factor-beta,

promoting brosis in NSF (57).
The clinical and pathological ndings of NSF are not
unique to this disease and must be correlated with histology to establish a diagnosis (49). Mimicking clinical
diagnoses should be excluded such as lipodermatosclero-

Fig. 12. Pseudoporphyria with a single tense bulla.

sis, chronic venous stasis, scleromyxedema, eosinophiic

fasciitis, morphea scleroderma, and chronic graftversus-host disease (49). There may be overlapping
histopathology with scleromyxedema, morhphea
scleroderma, eosinophilic fasciitis, scleredema, eosinophilic-myalgia syndrome, and lipodermatosclerosis (49).

DIAGNOSIS OF COMMON DERMOPATHIES IN DIALYSIS PATIENTS

There is no effective treatment for NSF; however,

improvement with topical or systemic corticosteroids,
cyclophosphamide, thalidomide, plasmapheresis, immunoglobulin infusion, imatinib mesylate, and rapamycin
has been reported (29,55). Physical therapy is integral in
minimizing the immobility due to joint involvement
(55).
Given the lack of successful treatment, prevention of
this disease is critical (50). Avoidance of triggers and risk
factor reduction may reduce incidence of NSF. Gadolinium agents should be used in ESRD patients only when
absolutely necessary with particular concern in those
with severe inammatory processes; the use of more stable gadolinium agents in reduced dosage and frequency
is advisable. Optimizing dialysis and employing alternative diagnostic modalities may serve a further preventative role. One Wisconsin center, which employed the
above preventative measures, noted no new cases of
NSF in a 4-year follow-up, as compared to six new NSF
cases in the year prior to the implementation of these
guidelines (50).
Porphyria Cutanea Tarda
Porphyria cutanea tarda (PCT), the most common
porphyria, is a multifactorial disorder caused by accumulation of uroporphyrinogens, which cause phototoxic skin reactions and asymptomatic liver involvement
(58). Porphyria cutanea tarda can occur in patients
with renal failure and those on dialysis. PCT has a
prevalence of 1:10,000 and affects males and females
approximately equally (59). Although PCT has historically been more common in men, the rise of oral contraceptives use and suspected role in the etiology of
PCT may explain the rising incidence of PCT in
women (59). PCT is a multifactorial disorder with sporadic (Type I) and familial (Type II) forms. About
75% of patients have sporadic PCT, presenting in middle age, whereas the remainder have familial PCT, presenting by age 20 (60). PCT has been observed in
patients with impaired renal function, undergoing
chronic peritoneal dialysis, or undergoing chronic hemodialysis. Incidence of PCT in hemodialysis patients
has been reported in the range of 1.218% (29).
PCT manifests as asymptomatic hepatic involvement
and phototoxic skin reactions, which result from free
radicals generated by porphyrins in the presence of UV
light (58). Accumulation of uroporphyrin, a photosensitive compound, in skin leads to skin fragility, vesicles,
and bullae in sun-exposed areas, especially on the dorsal
hands (59) (Figs. 911). External trauma to the blisters
results in erosions and crusting, and these lesions heal
with scarring and milia formation (29). Other clinical
manifestations of PCT include hypertrichosis, hyperpigmentation, dark urine, and pruritus (59). In sun-exposed
and protected skin, sclerodermoid changes can be seen
(29). Periorbital hypertrichosis is also frequently seen in
women and, along with facial hyperpigmentation, as an
initial sign of PCT in women (58).
PCT is characterized by subepidermal separation of
the skin. There is very little or no associated inamma-

415

tion. Caterpillar bodies, present intraepidermally, are

eosinophilic collections of basement membrane type IV
collagen. Immunoorescence of perilesional skin reveals
linear IgG, C3, and brinogen along the dermoepidermal junction and around blood vessels (29).
Familial PCT and sporadic PCT manifest when hepatic uroporphyrinogen decarboxylase (URO-D) has an
activity less than 30% of normal (61), resulting in accumulation of uroporphyrins in the skin and liver. Sporadic PCT is characterized by reduced hepatic URO-D
activity secondary to factors such as hemochromatosis
gene mutations, estrogens, high alcohol intake, hepatitis
C virus (HCV) infection, and human immunodeciency
virus (HIV) infection (61). Familial PCT is characterized
by a family-specic UROD gene defect leading to a
reduction in URO-D activity by 50% in all tissues.
Because hepatic URO-D activity must be reduced to
<30% of normal before clinical manifestations appear,
the same genetic and environmental factors contributing
to sporadic PCT are needed to induce clinical manifestations of familial PCT. However, a greater inactivation of
URO-D is required in sporadic PCT before symptoms
appear (62).
Virtually all patients with PCT also demonstrate iron
overload, as evidenced by their serum iron and serum
ferritin levels. Iron induces 5-aminolevulinate synthase,
a regulatory enzyme in heme biosynthesis, which suppresses the activity of URO-D (63). Additionally, iron
promotes oxidation of porphyrinogen precursors into
porphyrin (29).
P450 CYP1AA2 has been reported to convert uroporphyrinogen to uroporphomethene in an oxidative,
iron-dependent reaction and that uroporphomethene is
a competitive inhibitor of URO-D (64). It has also been
suggested that patients with a -162A A genotype of the
CYP1A2 gene may be at increased risk for PCT (62).
However, the frequency of this allele in patients with
symptomatic familial PCT and asymptomatic URO-D
mutation carriers has not been shown to be signicantly
different (62).
Development of PCT may occur in patients with
impaired renal function, if uroporphyrins are not efciently excreted. Patients undergoing chronic peritoneal
dialysis or hemodialysis may also develop PCT, if dialysis of porphyrins is not sufcient. Porphyrins, although
hydrophilic and of low molecular weight, may bind to
high molecular weight proteins such as albumin or hemoprexin, forming complexes that are not dialyzable
(65).
Urinary and stool porphyrin analyses are required to
distinguish PCT from other forms of porphyria, including variegate porphyria, hereditary coproporphyria,
mild variants of hepatoerythropoietic porphyria, and
congenital erythropoietic porphyria (59). Epidermolysis bullosa acquisita, polymorphous light eruption,
photoxic and bullous drug eruptions, and hydroa vacciniforme should be excluded as well (59). In PCT, uroporphyrin I, uroporphyrin II, 8-carboxyl uroporphyrin,
and 7-carboxyl porphyrin will be increased in urine (29).
Increased fecal isocoproporphyrin III and increased
plasma uroporphyrin are diagnostic. In patients with
renal failure, fecal analyses are most useful, as plasma

416

Markova et al.

uroporphyrin concentration is increased at baseline in

hemodialysis patients (60).
Photoprotection and avoidance of sunlight exposure
are important in managing PCT. Reducing iron overload in PCT patients has been shown to be effective in
management of symptoms. Phlebotomy has been shown
to be effective in depleting total iron body stores. However, removal of 250500 ml of blood 12 times per week
is not well tolerated by patients with renal failure due to
associated anemia in this population, which can occur
even in states of iron overload (63). Small volume phlebotomy (50100 ml once or twice a week) has been
reported to induce remission of PCT after 8 months of
therapy (29). Treatment with erythropoietin has also
been successful (63). Antimalarials, such as chloroquine
or hydroxychloroquine, have been reported to be effective in treatment of PCT, especially in patients without
marked iron overload (66). Of note, successful treatment
with chloroquine therapy has not been reported in anuric patients on dialysis (64). This is likely due to chloroquines action in increasing the solubility of porphyrins
leading to their greater excretion; however, these chloroquineporphyrin complexes are inefciently cleared in
anuric patients (67).

While the mechanism of PP development is unknown,

evidence supports the role of UV light in the pathogenesis of this condition, given that PP has been associated
with excessive UVA exposure and photosensitizing medications (69). In ESRD, patients on hemodialysis are
more susceptible to free-radical injury due to decreased
levels of the antioxidant glutathione in plasma and
erythrocytes (68).
Patients with PP do not exhibit the biochemical porphyrin abnormalities seen in patients with PCT.
Although serum, urinary, and fecal porphyrins may be
within normal ranges (74), up to 69% of patients on hemodialysis without any clinical manifestations of cutaneous disease have elevated plasma porphyrin levels (3).
Therefore, when the term pseudoporphyria is applied
to a patient on dialysis with cutaneous manifestations,
mildly elevated serum porphyrin can be expected (65).
Treatment of PP includes discontinuing any suspected
inciting agent and avoidance of UVA. Treatment with
N-acetylcysteine, which is believed to increase glutathione production, has been successful in patients with PP
associated with hemodialysis (68,70,75). Symptoms may
take months to resolve, despite treatment with N-acetylcysteine, and stopping the drug may cause symptoms to
recur (29).

Pseudoporphyria
Conclusions
Pseudoporphyria (PP), also known as bullous dermatosis of ESRD, is a photodermatosis that clinically and
histopathologically resembles porphyria cutanea tarda.
Like PCT, PP is seen in patients with chronic renal failure or undergoing long-term hemodialysis. However,
differentiation between patients with PP and patients
with PCT is possible through their different porphyrin
proles.
PP occurs in about 1.218% of patients with ESRD
on hemodialysis and less frequently in those on peritoneal dialysis (68,69). Development of PP has also been
associated with ultraviolet A (UVA) tanning beds,
psoralen UVA (PUVA), phototherapy with ultraviolet
B (UVB), and medications including diuretics, nonsteroidal antiinammatory drugs (e.g., naproxen), antibiotics, antifungal drugs (e.g., voriconazole), and
retinoids (6974). Recently, reports suggest that
pseudoporphyria can be induced by nasteride and imatinib mesylate (3,44).
PP and PCT both clinically present as skin fragility,
bullae on photo-exposed areas of the skin (especially on
the dorsal portions of forearms and hands), dystrophic
calcication, and milia (75) (Fig. 12). Unlike PCT, however, hypertrichosis and sclerodermoid changes are not
seen in PP (29,74).
Histopathological examination of lesional skin reveals
subepidermal, cell-poor, blister formation with intracorneal hemorrhages and no inammatory inltrate (68).
Mild perivascular lymphocytic inammation can be seen
in some patients, along with sclerosis of collagen (3).
Caterpillar bodies may be seen, mimicking PCT. In both
PP and PCT, direct immunoorescence reveals vascular
and junctional C3 and immunoglobulin deposits, but
direct immunoorescence may be negative (3,68).

Due to a range of differential diagnoses, carefully

considered patient history, clinical examination, and
laboratory evaluation are necessary to diagnose any
cutaneous abnormalities, which develop in patients
with ESRD receiving hemodialysis or peritoneal
dialysis.
Acknowledgments
We thank the following physicians for the use of their
clinical photographs:
Dr. Elnaz Firoz (Figs. 3 and 4); Dr. Kachiu Cecilia Lee
(Figs. 7 and 8), and Dr. Jessica Mercer (Figs. 5,911).

Financial Disclosures
None.

References
1. Udayakumar P, Balasubramanian S, Ramalingam KS, Lakshmi C,
Srinivas CR, Mathew AC: Cutaneous manifestations in patients with
chronic renal failure on hemodialysis. Indian J Dermatol Venereol Leprol 72(2):119125, 2006
2. Alston H, Burns A: Half and half nails. Nephrol Dial Transplant 4:361,
2011
3. Berghoff AT, English JC III: Imatinib mesylate-induced pseudoporphyria. J Am Acad Dermatol 63(1):e14e16, 2010
4. Kurban MS, Boueiz A, Kibbi AG: Cutaneous manifestations of chronic
kidney disease. Clin Dermatol 26(3):255264, 2008
5. Salem A, Al Mokadem S, Attwa E, Abd El Raoof S, Ebrahim HM,
Faheem KT: Nail changes in chronic renal failure patients under haemodialysis. J Eur Acad Dermatol Venereol 22(11):13261331, 2008

DIAGNOSIS OF COMMON DERMOPATHIES IN DIALYSIS PATIENTS

6. Kuo CC, Hung J, Tsai C, Chen Y: Uremic frost. CMAJ 182(17):E800,
2010
7. Pol-Rodriguez MM, Wanner M, Bhat P, Grossman ME: Uremic frost
in a critically ill patient. Kidney Int 73(6):790, 2008
8. Walsh SR, Parada NA: Images in clinical medicine. Uremic frost. N
Engl J Med 352(13):e13, 2005
9. Khanna D, Singal A, Kalra OP: Comparison of cutaneous manifestations in chronic kidney disease with or without dialysis. Postgrad Med J
86(1021):641647, 2010
10. Robinson-Bostom L, DiGiovanna JJ: Cutaneous manifestations of endstage renal disease. J Am Acad Dermatol 43(6): 975986, 2000; quiz
987990.
11. Amatya B, Agrawal S, Dhali T, Sharma Sanjib, Pandey SS: Pattern of
skin and nail changes in chronic renal failure in Nepal: a hospital-based
study. J Dermatol 35(3):140145, 2008
12. Szepietowski JC, Balaskas E, Taube K, Taberly A, Dupuy P: Quality of
life in patients with uraemic xerosis and pruritus. Acta Derm Venereol
91(3):313317, 2011
13. Avermaete A, Altmeyer P, Bacharach-Buhles M: Skin changes in dialysis patients: a review. Nephrol Dial Transplant 16(12):22932296, 2001
14. Falodun O, Ogunbiyi A, Salako B, George AK: Skin changes in
patients with chronic renal failure. Saudi J Kidney Dis Transpl
22(2):268272, 2011
15. Wang H, Yosipovitch G: New insights into the pathophysiology and
treatment of chronic itch in patients with end-stage renal disease,
chronic liver disease, and lymphoma. Int J Dermatol 49(1):111, 2010
16. Castello M, Milani M: Efcacy of topical hydating and emollient lotion
containin 10% urea ISDIN (R) plus dexpanthenol (Ureadin Rx 10) in
the treatmen of skin xerosis and pruritus in hemodialyzed patiens: an
open prospective pilot trial. Giornale Italiano di dermatologia e venerologia: organo ufciale, Societa italiana di dermatologia e silogaa.
146(5):321325, 2011
17. Sanai M, Aman S, Nadeem M, Kazmi AH: Dermatologic manifestations in patients of renal disease on haemodialysis. Journal of Pakistan
Association of Dermatologists 20:163168, 2010
18. Shibata M, Nagai K, Usami K, Tawada H, Taniguchi S: The quantitative evaluation of online haemodialtration effect on skin hyperpigmentation. Nephrol Dial Transplant 26(3):988992, 2011
19. Moon SJ, Kim DK, Chang JH, Kim CH, Kim HW, Park SY, Han SH,
Lee JE, Yoo TH, Han DS, Kang SW: The impact of dialysis modality
on skin hyperpigmentation in haemodialysis patients. Nephrol Dial
Transplant 24(9):28032809, 2009
20. Kocyigit I, Unal A, Tanriverdi F, Hayri Sipahioglu M, Tokgoz B,
Oymak O, Utas C: Misdiagnosis of Addisons disease in a patient with
end-stage renal disease. Ren Fail 33(1):8891, 2011
21. Kazmierowski JA, Chusid MJ, Parrillo JE, Fauci AS, Wolff SM:
Dermatologic manifestations of the hypereosinophilic syndrome. Arch
Dermatol 114(4):531535, 1978
22. Kho HS, Lee SW, Chung SC, Kim YK: Oral manifestations and salivary ow rate, pH, and buffer capacity in patients with end-stage renal
disease undergoing hemodialysis. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 88(3):316319, 1999
23. Kaw D, Malhotra D: Platelet dysfunction and end-stage renal disease.
Semin Dial 19(4):317322, 2006
24. Talalla A, Halbrook H, Barbour BH, Kurze T: Subdural hematoma
associated with long-term hemodialysis for chronic renal disease. JAMA
212(11):18471849, 1970
25. Sabovic M, Salobir B, Preloznik Zupan I, Bratina P, Bojec V, Buturovic
Ponikvar J: The inuence of the haemodialysis procedure on platelets,
coagulation and brinolysis. Pathophysiol Haemost Thromb 34(6):274
278, 2005
26. Heistinger M, Stockenhuber F, Schneider B, Pabinger I, Brenner B,
Wagner B, Balcke P, Lechner K, Kyrle PA: Effect of conjugated estrogens on platelet function and prostacyclin generation in CRF. Kidney
Int 38(6):11811186, 1990
27. Sriprakash K, Yong-Gee S: Multiple minute digitate hyperkeratoses
associated with paraproteinaemia. Australas J Dermatol 49(4):233236,
2008
28. Yang JH, Kim JK, Won CH, Chang SE, Lee MW, Choi JH, Moon KC:
Isolated epidermolytic acanthoma in a renal transplant recipient. Ann
Dermatol 23(3):415416, 2011
29. Cordova KB, Oberg TJ, Malik M, Robinson-Bostom L: Dermatologic
conditions seen in end-stage renal disease. Semin Dial 22(1):4555, 2009
30. Saray Y, Seckin D, Bilezikci B: Acquired perforating dermatosis: clinicopathological features in twenty-two cases. J Eur Acad Dermatol Venereol 20(6):679688, 2006
31. Karpouzis A, Giatromanolaki A, Sivridis E, Kouskoukis C: Acquired
reactive perforating collagenosis: current status. J Dermatol 37(7):585
592, 2010
32. Hari Kumar KV, Prajapati J, Pavan G, Parthasarathy A, Jha R, Modi
KD: Acquired perforating dermatoses in patients with diabetic kidney
disease on hemodialysis. Hemodial Int 14(1):7377, 2010
33. Lynde CB, Pratt MD: Clinical Images: acquired perforating dermatosis:
association with diabetes and renal failure. CMAJ 181(9):615, 2009

417

34. Sezer E, Erkek E: Acquired perforating dermatosis successfully treated

with photodynamic therapy. Photodermatol Photoimmunol Photomed
28(1):5052, 2012
35. Reiter N, El-Shabrawi L, Leinweber B, Berghold A, Aberer E: Calcinosis cutis: part I. Diagnostic pathway. J Am Acad Dermatol 65(1): 112;
2011, quiz 1314.
36. Tan O, Atik B, Kizilkaya A, Ozer E, Kavukcu S: Extensive skin calcications in an infant with chronic renal failure: metastatic calcinosis
cutis. Pediatr Dermatol 23(3):235238, 2006
37. Rivet J, Lebbe C, Urena P, Cordoliani F, Martinez F, Baglin AC,
Aubert P, Aractingi S, Ronco P, Fournier P, Janin A: Cutaneous calcication in patients with end-stage renal disease: a regulated process associated with in situ osteopontin expression. Arch Dermatol 142(7):900
906, 2006
38. Walsh JS, Fairley JA: Calcifying disorders of the skin. J Am Acad Dermatol 33(5 Pt 1): 693706, 1995; quiz 707710.
39. Chung SD, Lu CW, Wu VC, Chen YS, Chang KC, Chu SH: Metastatic
calcinosis cutis. QJM 102(5):359, 2009
40. Beus KS, Stack BC Jr: Calciphylaxis. Otolaryngol Clin North Am 37(4):
941948, xii, 2004.
41. Brewster UC: Dermatological disease in patients with CKD. Am J Kidney Dis 51(2):331344, 2008
42. Weenig RH, Sewell LD, Davis MD, McCarthy JT, Pittelkow MR: Calciphylaxis: natural history, risk factor analysis, and outcome. J Am
Acad Dermatol 56(4):569579, 2007
43. Brandenburg VM, Cozzolino M, Ketteler M: Calciphylaxis: a still
unmet challenge. J Nephrol 24(2):142148, 2011
44. Santo Domingo D, Stevenson ML, Auerbach J, Lerman J: Finasterideinduced pseudoporphyria. Arch Dermatol, 147(6):747748, 2011
45. Vedvyas C, Wintereld LS, Vleugels RA: Calciphylaxis: a systematic
review of existing and emerging therapies. J Am Acad Dermatol 2011.
Aug 5. [Epub ahead of print].
46. Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE:
Scleromyxoedema-like cutaneous diseases in renal-dialysis patients.
Lancet 356(9234):10001001, 2000
47. Cowper SE, Su LD, Bhawan J, Robin HS, LeBoit PE: Nephrogenic brosing dermopathy. Am J Dermatopathol 23(5):383393, 2001
48. Ting WW, Stone MS, Madison KC, Kurtz K: Nephrogenic brosing
dermopathy with systemic involvement. Arch Dermatol 139(7):903906,
2003
49. Girardi M, Kay J, Elston DM, Leboit PE, Abu-Alfa A, Cowper SE:
Nephrogenic systemic brosis: clinicopathological denition and
workup recommendations. J Am Acad Dermatol 65(6):10951106, 2011
50. Haemel AK, Sadowski EA, Shafer MM, Djamali A: Update on nephrogenic systemic brosis: are we making progress? Int J Dermatol
50(6):659666, 2011
51. Kendrick-Jones JC, Voss DM, De Zoysa JR: Nephrogenic systemic
brosis, in patients with end-stage kidney disease on dialysis, in the
greater Auckland region, from 2000-2006. Nephrology (Carlton)
16(2):243248, 2011
52. Deo A, Fogel M, Cowper SE: Nephrogenic systemic brosis: a population study examining the relationship of disease development to gadolinium exposure. Clin J Am Soc Nephrol 2(2):264267, 2007
53. Othersen JB, Maize JC, Woolson RF, Budisavljevic MN: Nephrogenic
systemic brosis after exposure to gadolinium in patients with renal failure. Nephrol Dial Transplant 22(11):31793185, 2007
54. Shabana WM, Cohan RH, Ellis JH, Hussain HK, Francis IR, Su LD,
Mukherji SK, Swartz RD: Nephrogenic systemic brosis: a report of 29
cases. AJR Am J Roentgenol 190(3):736741, 2008
55. Jalandhara N, Arora R, Batuman V: Nephrogenic systemic brosis and
gadolinium-containing radiological contrast agents: an update. Clin
Pharmacol Ther 89(6):920923, 2011
56. Nazarian RM, Mandal RV, Kagan A, Kay J, Duncan LM: Quantitative
assessment of dermal cellularity in nephrogenic systemic brosis: a diagnostic aid. J Am Acad Dermatol 64(4):741747, 2011
57. Gupta A, Shamseddin MK, Khaira A: Pathomechanisms of nephrogenic systemic brosis: new insights. Clin Exp Dermatol 36(7):763768,
2011
58. Munoz-Santos C, Guilabert A, Moreno N, To-Figueras J, Badenas C,
Darwich E, Herrero C: Familial and sporadic porphyria cutanea tarda:
clinical and biochemical features and risk factors in 152 patients. Medicine (Baltimore) 89(2):6974, 2010
59. Frank J, Poblete-Gutierrez P: Porphyria cutanea tarda when skin
meets liver. Best Pract Res Clin Gastroenterol 24(5):735745, 2010
60. Sarkany RP: The management of porphyria cutanea tarda. Clin Exp
Dermatol 26(3):225232, 2001
61. Thunell S, Harper P: Porphyrins, porphyrin metabolism, porphyrias.
III. Diagnosis, care and monitoring in porphyria cutanea tardasuggestions for a handling programme. Scand J Clin Lab Invest 60(7):561579,
2000
62. Tchernitchko D, Robreau AM, Lefebvre T, Lamoril J, Deybach JC,
Puy H: Comprehensive cytochrome P450 CYP1A2 gene analysis in
French caucasian patients with familial and sporadic porphyria cutanea
tarda. Br J Dermatol 166(2):425429, 2012

418

Markova et al.

63. Shieh S, Cohen JL, Lim HW: Management of porphyria cutanea tarda
in the setting of chronic renal failure: a case report and review. J Am
Acad Dermatol 42(4):645652, 2000
64. Phillips JD, Bergonia HA, Reilly CA, Franklin MR, Kushner JP: A
porphomethene inhibitor of uroporphyrinogen decarboxylase causes
porphyria cutanea tarda. Proc Natl Acad Sci USA 104(12):50795084,
2007
65. Ryali ME, Whittier WL: Bullous skin lesions in a patient undergoing
chronic hemodialysis. Semin Dial 23(1):8387, 2010
66. Sassa S: Modern diagnosis and management of the porphyrias. Br J
Haematol 135(3):281292, 2006
67. Munoz-Santos C, Guilabert A, Moreno N, Gimenez M, Darwich E,
To-Figueras J, Herrero C: The association between porphyria cutanea
tarda and diabetes mellitus: analysis of a long-term follow-up cohort. Br
J Dermatol 165(3):486491, 2011
68. Massone C, Ambros-Rudolph CM, Di Stefani A, Mullegger RR: Successful outcome of haemodialysis-induced pseudoporphyria after shortterm oral N-acetylcysteine and switch to high-ux technique dialysis.
Acta Derm Venereol 86(6):538540, 2006

69. Cooke NS, McKenna K: A case of haemodialysis-associated pseudoporphyria successfully treated with oral N-acetylcysteine. Clin Exp Dermatol 32(1):6466, 2007
70. Guiotoku MM, Pereira Fde P, Miot HA, Marques ME: Pseudoporphyria induced by dialysis treated with oral N-acetylcysteine. An Bras Dermatol 86(2):383385, 2011
71. Kwong WT, Hsu S: Pseudoporphyria associated with voriconazole. J
Drugs Dermatol 6(10):10421044, 2007
72. Riahi RR, Cohen PR: Voriconazole-associated phototoxicity. Dermatol
Online J 17(2):15, 2011
73. Sharp MT, Horn TD: Pseudoporphyria induced by voriconazole. J Am
Acad Dermatol 53(2):341345, 2005
74. Tolland JP, McKeown PP, Corbett JR: Voriconazole-induced pseudoporphyria. Photodermatol Photoimmunol Photomed 23(1):2931, 2007
75. Felix RH, Silva MF Jr, Almeida JB, Neto PB: Pseudoporphyria associated with hemodialysis. Kidney Int 79(1):140, 2011